{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T11:14:42Z","timestamp":1791458082863,"version":"4.3.4"},"reference-count":80,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T00:00:00Z","timestamp":1695859200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID2019\u2010105128RB\u2010I00"],"award-info":[{"award-number":["PID2019\u2010105128RB\u2010I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["SAF2016\u201076338\u2010R"],"award-info":[{"award-number":["SAF2016\u201076338\u2010R"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004410","name":"European Molecular Biology Organization","doi-asserted-by":"publisher","award":["9290"],"award-info":[{"award-number":["9290"]}],"id":[{"id":"10.13039\/100004410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010067","name":"Gobierno de Arag\u00f3n","doi-asserted-by":"publisher","award":["B31_20R"],"award-info":[{"award-number":["B31_20R"]}],"id":[{"id":"10.13039\/501100010067","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100023561","name":"Ministerio de Universidades","doi-asserted-by":"publisher","award":["FPU17\/02586"],"award-info":[{"award-number":["FPU17\/02586"]}],"id":[{"id":"10.13039\/501100023561","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:p>A better understanding of multiple myeloma (MM) biology has led to the development of novel therapies. However, MM is still an incurable disease and new pharmacological strategies are needed. Dinaciclib, a multiple cyclin\u2010dependent kinase (CDK) inhibitor, which inhibits CDK1, 2, 5 and 9, displays significant antimyeloma activity as found in phase II clinical trials. In this study, we have explored the mechanism of dinaciclib\u2010induced death and evaluated its enhancement by different BH3 mimetics in MM cell lines as well as in plasma cells from MM patients. Our results indicate a synergistic effect of dinaciclib\u2010based combinations with B\u2010cell lymphoma 2 or B\u2010cell lymphoma extra\u2010large inhibitors, especially in MM cell lines with partial dependence on myeloid cell leukemia sequence 1 (MCL\u20101). Simultaneous treatment with dinaciclib and BH3 mimetics ABT\u2010199 or A\u20101155463 additionally showed a synergistic effect in plasma cells from MM patients, <jats:italic>ex\u2009vivo<\/jats:italic>. Altered MM cytogenetics did not affect dinaciclib response <jats:italic>ex\u2009vivo<\/jats:italic>, alone or in combined treatment, suggesting that these combinations could be a suitable therapeutic option for patients bearing cytogenetic alterations and poor prognosis. This work also opens the possibility to explore cyclin\u2010dependent kinase 9 inhibition as a targeted therapy in MM patients overexpressing or with high dependence on MCL\u20101.<\/jats:p>","DOI":"10.1002\/1878-0261.13522","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T02:55:09Z","timestamp":1694660109000},"page":"2507-2525","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Dinaciclib synergizes with <scp>BH3<\/scp> mimetics targeting <scp>BCL<\/scp>\u20102 and <scp>BCL\u2010X<sub>L<\/sub><\/scp> in multiple myeloma cell lines partially dependent on <scp>MCL<\/scp>\u20101 and in plasma cells from patients"],"prefix":"10.1002","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7977-8020","authenticated-orcid":false,"given":"Manuel","family":"Beltr\u00e1n\u2010Visiedo","sequence":"first","affiliation":[{"name":"Apoptosis, Immunity &amp; Cancer Group, IIS Arag\u00f3n University of Zaragoza  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0381-3292","authenticated-orcid":false,"given":"Nelia","family":"Jim\u00e9nez\u2010Aldu\u00e1n","sequence":"additional","affiliation":[{"name":"Apoptosis, Immunity &amp; Cancer Group, IIS Arag\u00f3n University of Zaragoza  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosana","family":"D\u00edez","sequence":"additional","affiliation":[{"name":"Apoptosis, Immunity &amp; Cancer Group, IIS Arag\u00f3n University of Zaragoza  Spain"},{"name":"Hematology Service Hospital Universitario Miguel Servet  Zaragoza Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2261-7792","authenticated-orcid":false,"given":"Marta","family":"Cuenca","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht Utrecht University  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8581-8260","authenticated-orcid":false,"given":"Andrea","family":"Benedi","sequence":"additional","affiliation":[{"name":"Apoptosis, Immunity &amp; Cancer Group, IIS Arag\u00f3n University of Zaragoza  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9343-1050","authenticated-orcid":false,"given":"Alfonso","family":"Serrano\u2010Del Valle","sequence":"additional","affiliation":[{"name":"Apoptosis, Immunity &amp; Cancer Group, IIS Arag\u00f3n University of Zaragoza  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5068-7355","authenticated-orcid":false,"given":"Gemma","family":"Azaceta","sequence":"additional","affiliation":[{"name":"Hematology Service Hospital Cl\u00ednico Universitario Lozano Blesa  Zaragoza Spain"},{"name":"HCU\u2010Lozano Blesa\u2010Hematology Research Group, IIS Arag\u00f3n Instituto Aragon\u00e9s de Ciencias de la Salud  Zaragoza Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8515-3599","authenticated-orcid":false,"given":"Luis","family":"Palomera","sequence":"additional","affiliation":[{"name":"Hematology Service Hospital Cl\u00ednico Universitario Lozano Blesa  Zaragoza Spain"},{"name":"HCU\u2010Lozano Blesa\u2010Hematology Research Group, IIS Arag\u00f3n Instituto Aragon\u00e9s de Ciencias de la Salud  Zaragoza Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9011-3820","authenticated-orcid":false,"given":"Victor","family":"Peperzak","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology, University Medical Center Utrecht Utrecht University  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5175-8394","authenticated-orcid":false,"given":"Alberto","family":"Anel","sequence":"additional","affiliation":[{"name":"Apoptosis, Immunity &amp; Cancer Group, IIS Arag\u00f3n University of Zaragoza  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2156-8378","authenticated-orcid":false,"given":"Javier","family":"Naval","sequence":"additional","affiliation":[{"name":"Apoptosis, Immunity &amp; Cancer Group, IIS Arag\u00f3n University of Zaragoza  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2315-9079","authenticated-orcid":false,"given":"Isabel","family":"Marzo","sequence":"additional","affiliation":[{"name":"Apoptosis, Immunity &amp; Cancer Group, IIS Arag\u00f3n University of Zaragoza  Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,28]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.46"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41408-021-00587-0"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2019.00050"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-05-573741"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2016.53"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsob.180112"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1829"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/1765182"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22062935"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.19589"},{"issue":"3","key":"e_1_2_11_12_1","first-page":"390","article-title":"Flavopiridol in patients with relapsed or refractory multiple myeloma: a phase 2 trial with clinical and pharmacodynamic end\u2010points","volume":"91","author":"Dispenzieri A","year":"2006","journal-title":"Haematologica"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-011-1039-4"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30095-4"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.2217\/fon-2020-1264"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.12.006"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers7010179"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-10-0324"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2015.10"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.183"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2015.05.014"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19830"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.01.037"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.01.018"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-788786"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2019.02.007"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30525-8"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2020.100672"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-018-0183-7"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0201-2"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/ml5001867"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41389-018-0084-0"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-40106-7"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2011.11.021"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2008.11.024"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(86)90368-6"},{"key":"e_1_2_11_37_1","article-title":"Generation of genomic deletions in mammalian cell lines via CRISPR\/Cas9","volume":"95","author":"Bauer DE","year":"2015","journal-title":"J Vis Exp"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2009.143"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2014.117531"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020003731"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12061694"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad001"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1947"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2013.139"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-1853"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01205"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-3670"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-03-704908"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-03-836718"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12032-021-01636-1"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.678559"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.2538"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14285"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.13191"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.103950"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10061360"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2019-121845"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2016.08.019"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00407-4"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2505-1"},{"key":"e_1_2_11_61_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2018.212308"},{"key":"e_1_2_11_62_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-08-0655"},{"key":"e_1_2_11_63_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-19-0451"},{"key":"e_1_2_11_64_1","doi-asserted-by":"publisher","DOI":"10.1002\/med.21379"},{"key":"e_1_2_11_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.432"},{"key":"e_1_2_11_66_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2022.281443"},{"key":"e_1_2_11_67_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-04-1678"},{"key":"e_1_2_11_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403784"},{"key":"e_1_2_11_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-021-00869-x"},{"key":"e_1_2_11_70_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000702"},{"key":"e_1_2_11_71_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-03-009910"},{"key":"e_1_2_11_72_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2021.278888"},{"key":"e_1_2_11_73_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-1066"},{"key":"e_1_2_11_74_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0202-1"},{"key":"e_1_2_11_75_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2013.04.006"},{"key":"e_1_2_11_76_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-022-00333-0"},{"key":"e_1_2_11_77_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-00928-9"},{"key":"e_1_2_11_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101015"},{"key":"e_1_2_11_79_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.215855.113"},{"key":"e_1_2_11_80_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.215871.113"},{"key":"e_1_2_11_81_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0234103"}],"container-title":["Molecular Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.13522","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T11:51:48Z","timestamp":1703245908000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/1878-0261.13522"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,28]]},"references-count":80,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["10.1002\/1878-0261.13522"],"URL":"https:\/\/doi.org\/10.1002\/1878-0261.13522","archive":["Portico"],"relation":{},"ISSN":["1574-7891","1878-0261"],"issn-type":[{"value":"1574-7891","type":"print"},{"value":"1878-0261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,28]]},"assertion":[{"value":"2023-05-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-12","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}